This is an application to establish a Conte Center for Neuroscience Research on the FUNCTIONAL CIRCUITRY OF THE HIPPOCAMPUS. The overall objective is to elucidate the nature of neural processing in the hippocampus and related cortical structures that mediate episodic memory. Our hypothesis is that the hippocampus, together with associated cortical areas, represents sequential events that compose and distinguish episodes. This project provides the first systematic examination of that hypothesis and challenges three prominent alternate views, that memory for order is a reflection of a general associative function of the hippocampus, that the hippocampus is specialized for spatial memory, and that temporal organization of memory is accomplished by other brain areas. Our approach involves different levels of biological organization and combines multiple disciplinary, methodological, and technological perspectives integrated across four projects. Studies on human functional brain imaging will characterize the scope of sequence representation in which the hippocampus is involved, identify interactions between the hippocampus and cortical networks, and distinguish the role of the hippocampus from that of other brain areas involved in sequence representation. Studies on the activity of neural ensembles and rhythmic field potentials in behaving animals will identify neural coding mechanisms for temporal organization of nonspatial and spatial memory in hippocampal and cortical subregions. Computational studies will model behavior and spike timing, revealing basic features of circuit processing and rhythmic activity in the encoding and retrieval of sequential information. The human and animal studies emphasize the strengths of each approach and close parallels in experimental design between species. The experimental and computational projects are highly interactive and co-dependent, designed to provide a circuit level accounting of neural representation and cognitive performance. The combined research is aimed to provide a breakthrough in our understanding of the neural mechanisms of episodic memory and its deterioration associated with aging, brain damage, and disease.